Acute Slow Wave Responses to High-Frequency Gastric Electrical Stimulation in Patients With Gastroparesis Defined by High-Resolution Mapping.

BACKGROUND AND AIMS: High-frequency gastric electrical stimulation (GES) has emerged as a therapy for gastroparesis, but the mechanism(s) of action remain unclear. There is a need to refine stimulation protocols for clinical benefit, but a lack of accurate techniques for assessing mechanisms in clinical trials, such as slow wave modulation, has hindered progress. We thereby aimed to assess acute slow wave responses to GES in gastroparesis patients using high-resolution (HR) (multi-electrode) mapping, across a range of stimulation doses achievable by the Enterra stimulation device (Medtronic Inc., MN, USA). MATERIALS AND METHODS: Patients with medically refractory gastroparesis (n = 8) undergoing device implantation underwent intraoperative HR mapping (256 electrodes). Baseline recordings were followed by four protocols of increasing stimulation intensity, with washout periods. Slow wave patterns, frequency, velocity, amplitude, and dysrhythmia rates were quantified by investigators blinded to stimulation settings. RESULTS: There was no difference in slow wave pattern, frequency, velocity, or amplitude between baseline, washout, and stimulation periods (all p > 0.5). Dysrhythmias included ectopic pacemakers, conduction blocks, retrograde propagation, and colliding wavefronts, and dysrhythmia rates were unchanged with stimulation off vs. on (31% vs. 36% duration dysrhythmic; p > 0.5). Symptom scores and gastric emptying were improved at 5.8 month follow-up (p < 0.05). CONCLUSIONS: High-frequency GES protocols achievable from a current commercial device did not acutely modulate slow wave activity or dysrhythmias. This study advances clinical methods for identifying and assessing therapeutic GES parameters, and can be applied in future studies on higher-energy protocols and devices.

A Novel Gastric Pacing Device to Modulate Slow Waves and Assessment by High-Resolution Mapping.

OBJECTIVE: The use of electrical pacing in the gastrointestinal field continues to advance clinical and basic science; however, the efficacy and effectiveness of gastric stimulation and pacing remains limited. In the stomach, rhythmic bioelectrical events, known as slow waves, coordinate the muscular contractions that aid digestion. A range of slow wave abnormalities have been shown to be associated with functional motility disorders, such as gastroparesis, chronic unexplained nausea and vomiting, and functional dyspepsia. Pacing is an attractive therapeutic approach to revert slow wave abnormalities. However, there are currently no clinical gastric pacing devices in active use. In this study, a novel battery-powered pacing device was developed, implementing wireless control and tissue electrical parameter monitoring. METHODS: The pacing device was applied in five pigs in vivo along with high-resolution (HR) mapping to validate the device and to elucidate the pacing response of slow waves. The pacing leads were placed in the middle of the HR array to determine any changes to the propagation pattern. The pacing period range was 14-30 s. RESULTS: In all studies, the novel pacing device initiated slow wave activation from a location near the pacing leads at the specified period. Slow wave propagation speed increased after pacing (from 6.4 ± 2.0 to 8.1 ± 3.2 mm/s; P < 0.001), commensurate with induction of paced anisotropic propagation. CONCLUSION: This study introduces a novel gastric pacing system suitable for clinical trials, achieving reliable induction of slow wave pacing at specific location and periods. The device is now available to be trialed as a therapeutic application for motility disorders and obesity.

A Miniature Configurable Wireless System for Recording Gastric Electrophysiological Activity and Delivering High-Energy Electrical Stimulation.

The purpose of this paper is to develop and validate a miniature system that can wirelessly acquire gastric electrical activity called slow waves, and deliver high energy electrical pulses to modulate its activity. The system is composed of a front-end unit, and an external stationary back-end unit that is connected to a computer. The front-end unit contains a recording module with three channels, and a single-channel stimulation module. Commercial off-the-shelf components were used to develop front- and back-end units. A graphical user interface was designed in LabVIEW to process and display the recorded data in real-time, and store the data for off-line analysis. The system was successfully validated on bench top and in vivo in porcine models. The bench-top studies showed an appropriate frequency response for analog conditioning and digitization resolution to acquire gastric slow waves. The system was able to deliver electrical pulses at amplitudes up to 10 mA to a load smaller than 880 Ω. Simultaneous acquisition of the slow waves from all three channels was demonstrated in vivo. The system was able to modulate -by either suppressing or entraining- the slow wave activity. This study reports the first high-energy stimulator that can be controlled wirelessly and integrated into a gastric bioelectrical activity monitoring system. The system can be used for treating functional gastrointestinal disorders.

Design and application of a novel gastric pacemaker.

Omnipresent bioelectrical events known as slow waves are responsible for coordinating motility in the gastrointestinal tract. Functional motility diseases, such as gastroparesis, are associated with slow wave dysrhythmias. Electrical stimulation is a potential therapy to correct abnormal slow wave patterns. We present the design and application of a new gastric pacemaker. Real-time changes to the stimulation parameters such as period, amplitude and pulse width were applied using a graphical user interface, which communicated with the microcontroller to deliver the stimulus. The new pacemaker allows the voltage, delivered current and resistance between pacing electrodes to be continuously monitored. The pacing device was applied experimentally and was able to modulate and entrain gastric slow wave activity. After the onset of pacing, the direction of slow wave propagation was altered. Furthermore, the mean velocity and amplitude of slow wave activity increased from 4.7±1.5 to 5.4±1.3 mm/s, and from 1.1±1.1 to 1.7±0.9 mV, respectively. A simplified bidomain electrical model was used to simulate the recorded stimulus artifact. The model illustrated a new approach to evaluate if the stimulus has been delivered to the gastric tissue. The new pacing device and model will be used to investigate the mechanisms that allow pacing to entrain slow wave activity.

A framework for simulating gastric electrical propagation in confocal microscopy derived geometries.

Interstitial Cells of Cajal (ICC) initiate and actively propagate electrical events in the gastrointestinal tract known as slow-waves. The slow-waves coordinate the contraction of the gastrointestinal tract necessary for breakdown and mixing of ingested food. Degradation of the ICC numbers has been linked to several gastrointestinal motility disorders. However, limitations in imaging techniques and techniques for the quantification of ICC network structure have hindered our understanding of these disorders. We evaluated different machine learning techniques to segment ICC networks imaged using confocal microscopy. The accuracy the segmented networks were then quantified and compared using numerical metrics. Structurally realistic finite element meshes were constructed and used to simulate the propagation of electrical activation over the tissue blocks. The presented framework provides a system to quantify the structure and function of an ICC tissue sample. These methods are also applicable to other biological tissues and networks.

Progress in Mathematical Modeling of Gastrointestinal Slow Wave Abnormalities.

Gastrointestinal (GI) motility is regulated in part by electrophysiological events called slow waves, which are generated by the interstitial cells of Cajal (ICC). Slow waves propagate by a process of "entrainment," which occurs over a decreasing gradient of intrinsic frequencies in the antegrade direction across much of the GI tract. Abnormal initiation and conduction of slow waves have been demonstrated in, and linked to, a number of GI motility disorders. A range of mathematical models have been developed to study abnormal slow waves and applied to propose novel methods for non-invasive detection and therapy. This review provides a general outline of GI slow wave abnormalities and their recent classification using multi-electrode (high-resolution) mapping methods, with a particular emphasis on the spatial patterns of these abnormal activities. The recently-developed mathematical models are introduced in order of their biophysical scale from cellular to whole-organ levels. The modeling techniques, main findings from the simulations, and potential future directions arising from notable studies are discussed.

Tissue specific simulations of interstitial cells of cajal networks using unstructured meshes.

Gastrointestinal motility is facilitated by specialized pacemaker cells called Interstitial Cells of Cajal (ICC). ICC play a critical role in coordinating normal motility and its degradation in the gastrointestinal tract is associated with many functional motility disorders. Nonetheless, the degree of degradation and associated clinical impact remains unclear. Continuum modeling frameworks offers a virtual mean to simulate the electrical activity, and analyze the ICC activity in both normal and diseased states. Confocal images of the ICC networks were obtained from the intestine of normal mice. In this study, a new approach is presented where meshes of ICC networks were generated using a Delaunay triangulation and used to solve finite-element based reaction-diffusion equations describing gastrointestinal electrophysiology. The electrical activity was simulated on the ICC network and solutions were compared to those of a regular mesh based on individual pixel locations. The simulation results showed the proposed approach to be approximately 80% more efficient than a pixel-based mesh. The difference in activation time for the entire network between the different methods was observed to be around 4% (about 20 ms). The proposed approach will enable efficient examination of the ICC slow wave activity in larger networks and for longer temporal duration that has been previously impossible. This will provide valuable insights relating ICC degradation to gastrointestinal motility disorders.

A comparison of solver performance for complex gastric electrophysiology models.

Computational techniques for solving systems of equations arising in gastric electrophysiology have not been studied for efficient solution process. We present a computationally challenging problem of simulating gastric electrophysiology in anatomically realistic stomach geometries with multiple intracellular and extracellular domains. The multiscale nature of the problem and mesh resolution required to capture geometric and functional features necessitates efficient solution methods if the problem is to be tractable. In this study, we investigated and compared several parallel preconditioners for the linear systems arising from tetrahedral discretisation of electrically isotropic and anisotropic problems, with and without stimuli. The results showed that the isotropic problem was computationally less challenging than the anisotropic problem and that the application of extracellular stimuli increased workload considerably. Preconditioning based on block Jacobi and algebraic multigrid solvers were found to have the best overall solution times and least iteration counts, respectively. The algebraic multigrid preconditioner would be expected to perform better on large problems.

A Multiscale Tridomain Model for Simulating Bioelectric Gastric Pacing.

GOAL: Gastric motility disorders have been associated with abnormal slow wave electrical activity (gastric dysrhythmias). Gastric pacing is a potential therapy for gastric dysrhythmias; however, new pacing protocols are required that can effectively modulate motility patterns, while being power efficient. This study presents a novel comprehensive 3-D multiscale modeling framework of the human stomach, including anisotropic conduction, capable of evaluating pacing strategies. METHODS: A high-resolution anatomically realistic mesh was generated from CT images taken from a human stomach. Principal conduction axes were calculated and embedded within this model based on a modified Laplace-Dirichlet rule-based algorithm. A continuum-based tridomain formulation was implemented and evaluated for performance and used to model the slow-wave propagation, which takes into account the two main cell types present in gastric musculature. Model parameters were found by matching predicted normal slow-wave activity to experimental observation and data. These simulation parameters were applied while modeling an external pacing event to entrain slow-wave patterns. RESULTS: The proposed formulation was found to be two times more efficient than a previous formulation for a normal slow-wave simulation. Convergence analysis showed that a mesh resolution of [Formula: see text] is required for an accurate solution process. CONCLUSION: The effect of different pacing frequencies on entrainment demonstrated that the pacing protocols are limited by the frequency of the native propagation and the refractory period of the cellular activity. SIGNIFICANCE: The model is expected to become an important tool in studying pacing protocols for both efficiency and effectiveness.

A Stochastic Algorithm for Generating Realistic Virtual Interstitial Cell of Cajal Networks.

Interstitial cells of Cajal (ICC) play a central role in coordinating normal gastrointestinal (GI) motility. Depletion of ICC numbers and network integrity contributes to major functional GI motility disorders. However, the mechanisms relating ICC structure to GI function and dysfunction remains unclear, partly because there is a lack of large-scale ICC network imaging data across a spectrum of depletion levels to guide models. Experimental imaging of these large-scale networks remains challenging because of technical constraints, and hence, we propose the generation of realistic virtual ICC networks in silico using the single normal equation simulation (SNESIM) algorithm. ICC network imaging data obtained from wild-type (normal) and 5-HT2B serotonin receptor knockout (depleted ICC) mice were used to inform the algorithm, and the virtual networks generated were assessed using ICC network structural metrics and biophysically-based computational modeling. When the virtual networks were compared to the original networks, there was less than 10% error for four out of five structural metrics and all four functional measures. The SNESIM algorithm was then modified to enable the generation of ICC networks across a spectrum of depletion levels, and as a proof-of-concept, virtual networks were successfully generated with a range of structural and functional properties. The SNESIM and modified SNESIM algorithms, therefore, offer an alternative strategy for obtaining the large-scale ICC network imaging data across a spectrum of depletion levels. These models can be applied to accurately inform the physiological consequences of ICC depletion.

A biophysically based finite-state machine model for analyzing gastric experimental entrainment and pacing recordings.

Gastrointestinal motility is coordinated by slow waves (SWs) generated by the interstitial cells of Cajal (ICC). Experimental studies have shown that SWs spontaneously activate at different intrinsic frequencies in isolated tissue, whereas in intact tissues they are entrained to a single frequency. Gastric pacing has been used in an attempt to improve motility in disorders such as gastroparesis by modulating entrainment, but the optimal methods of pacing are currently unknown. Computational models can aid in the interpretation of complex in vivo recordings and help to determine optimal pacing strategies. However, previous computational models of SW entrainment are limited to the intrinsic pacing frequency as the primary determinant of the conduction velocity, and are not able to accurately represent the effects of external stimuli and electrical anisotropies. In this paper, we present a novel computationally efficient method for modeling SW propagation through the ICC network while accounting for conductivity parameters and fiber orientations. The method successfully reproduced experimental recordings of entrainment following gastric transection and the effects of gastric pacing on SW activity. It provides a reliable new tool for investigating gastric electrophysiology in normal and diseased states, and to guide and focus future experimental studies.

Developmental changes in postnatal murine intestinal interstitial cell of Cajal network structure and function.

The mammalian gastrointestinal (GI) tract undergoes rapid development during early postnatal life in order to transition from a milk to solid diet. Interstitial cells of Cajal (ICC) are the pacemaker cells that coordinate smooth muscle contractility within the GI tract, and hence we hypothesized that ICC networks undergo significant developmental changes during this early postnatal period. Numerical metrics for quantifying ICC network structural properties were applied on confocal ICC network imaging data obtained from the murine small intestine at various postnatal ages spanning birth to weaning. These imaging data were also coupled to a biophysically-based computational model to simulate pacemaker activity in the networks, to quantify how changes in structure may alter function. The results showed a pruning-like mechanism which occurs during postnatal development, and the temporal course of this phenomenon was defined. There was an initial ICC process overgrowth to optimize network efficiency and increase functional output volume. This was followed by a selective retaining and strengthening of processes, while others were discarded to further elevate functional output volume. Subsequently, new ICC processes were formed and the network was adjusted to its adult morphology. These postnatal ICC network developmental events may be critical in facilitating mature digestive function.

Toward the virtual stomach: progress in multiscale modeling of gastric electrophysiology and motility.

Experimental progress in investigating normal and disordered gastric motility is increasingly being complimented by sophisticated multiscale modeling studies. Mathematical modeling has become a valuable tool in this effort, as there is an ever-increasing need to gain an integrative and quantitative understanding of how physiological mechanisms achieve coordinated functions across multiple biophysical scales. These interdisciplinary efforts have been particularly notable in the area of gastric electrophysiology, where they are beginning to yield a comprehensive and integrated in silico organ modeling framework, or 'virtual stomach'. At the cellular level, a number of biophysically based mathematical cell models have been developed, and these are now being applied in areas including investigations of gastric electrical pacemaker mechanisms, smooth muscle electrophysiology, and electromechanical coupling. At the tissue level, micro-structural models are being creatively developed and employed to investigate clinically significant questions, such as the functional effects of ICC degradation on gastrointestinal (GI) electrical activation. At the organ level, high-resolution electrical mapping and modeling studies are combined to provide improved insights into normal and dysrhythmic gastric electrical activation. These efforts are also enabling detailed forward and inverse modeling studies at the 'whole body' level, with implications for diagnostic techniques for gastric dysrhythmias. These recent advances, together with several others highlighted in this review, collectively demonstrate a powerful trend toward applying mathematical models to effectively investigate structure-function relationships and overcome multiscale challenges in basic and clinical GI research.